抗菌性胜肽在許多的植物、昆蟲及哺乳動物之天生固有的防禦機制中扮演著重要的角色。絕大多數的抗菌性胜肽攻擊病原體並沒有藉由特定目標的受器，而是藉由與微生物細胞膜的相互接觸和穿透作用來破壞微生物的正常生長。隨著微生物抗藥性的增加、變強，發展有效性抗菌性胜肽是一新穎治療的方式來克服此細菌抗藥性問題。
在一系列胜肽庫中我們找到一新型的富含色氨酸(Trp-rich)的胜肽，序列為Ac-KWRRWVRWI-NH2，命名為Pac-525，此胜肽有較好的抗菌活性不管是對格蘭氏陽性(Gram positive)或陰性(negative)的細菌。對於Pac-525，我們做了多種的生物物理及化學的實驗證明此胜肽與帶負電的磷酸脂質有較強的相互吸引力、也較有效的釋放在帶負電的磷酸脂質內的染劑。我們同時也使用核磁共振儀來測定Pac-525結合擬態的膜SDS微胞(micelles)之結構。Pac-525結合SDS微胞之結構在殘基Trp2、Arg3和Arg4呈現一段□螺旋。Pac-525中帶正電的殘基群集一起形成一親水性區(patch)；三個疏水性殘基包括Trp2、Val6 和Ile9形成一疏水性核心(core)。在表面靜電電位圖(surface electrostatic potential map)表現出三個色氨酸引朵(indole)環堆疊成一雙極性(amphipathic)結構。此外，一些Pac-525衍生類似物，Pac-525rev，序列為Ac-IWRVWRRWK-NH2和D-Pac-525及 D-Nal-Pac-525同樣也對於格蘭氏陽性或陰性菌具有抗菌效力；D-Nal-Pac-525並且同時具有較好的抗真菌(antifungi)效能但其溶血性(haemolysis)較高。我們針對D-Nal-Pac-525測定其在DPC微胞結合的結構，在殘基Lys1、Nal2、Arg3、Arg4、Nal5、Val6和Arg7形成一段□螺旋，D-Nal-Pac-525也同樣呈現一雙極性(amphipathic)結構；所有的疏水性殘基包括Nal2、Nal5、Val6、Nal8和Ile9形成一疏水性核心(core)。用電子顯微鏡觀察Pac-525、D-Pac-525和D-Nal-Pac-525分別與大腸桿菌之間的相互作用，從顯現影像結果可得知這些胜肽的確對細菌的膜有作用且它們的對膜的作用方式可能不同。我們實驗結果指出對抗菌活性而言Pac-525的對掌性質並不重要但□-naphthylalanine分子的芳香環會使得Pac-525變得對真核膜更有特定性。
Src homology 2 (SH2)區塊(domains)在許多種訊息傳遞路徑扮演很重要的角色，而Growth factor receptor-bound protein 2 (Grb2)是一個轉接蛋白被發現可以和多種控制細胞分裂、成長的蛋白質相結合作用。因此Grb2 SH2區塊被許多科學家選擇作為治療乳癌和其他人類癌症的目標蛋白來發展有效的藥劑。在此論文中敘述針對Grb2 SH2區塊設計的非磷酸化(nonphosphorylated)胜肽抑制物，有直線性(linear)的四胜肽(tetrapeptides)及硫醚環化(thioether cyclized)胜肽。 使用表面電漿共振技術(surface plasmon resonance technology，SPR)來測定直線性的四胜肽，序列為Fmoc-X-Y-Aib-N-amide對Grb2 SH2區塊抑制效力。使用核磁共振想了解硫醚環化胜肽G1TE本身及其類似物G1TE(Gla1)與Grb2 SH2區塊複合結構。直到目前，我們還沒完成G1TE(Gla1)與Grb2 SH2區塊複合結構，現在仍持續進行中。從這些研究結果希望可以改善及發展針對Grb2 SH2區塊更有效用的抑制劑。

Antimicrobial peptides play important roles in the host innate defense mechanism of many plants, insects, and mammals. Most antimicrobial peptides do not target specific molecular receptors of the pathogens, but rather interact and permeabilize microbial membranes. With an increase of antibiotic resistance within bacteria, the potential for the development of antimicrobial peptides as novel therapeutic agents could overcome the problem of resistance
A new type of Trp-rich peptide, Ac-KWRRWVRWI-NH2, designated as Pac-525, was found to possess improved activity against both Gram positive and negative bacteria. The variety of biophysical and biochemical experiments, including circular dichroism, fluorescence spectroscopy and microcalorimetry, were used to show that Pac-525 interacted strongly with negatively charged phospholipid vesicles and induced efficient dye release from these vesicles. We have determined the solution structures of Pac-525 bound to membrane-mimetic SDS micelles. The SDS micelle-bound structure of Pac-525 adopts an □-helical segment at residues Trp2, Arg3 and Arg4. The positively charged residues are clustered together to form a hydrophilic patch. The three hydrophobic residues including Trp2, Val6, and Ile9 form a hydrophobic core. The surface electrostatic potential map indicates the three tryptophan indole rings are packed against the peptide backbone and form an amphipathic structure. Moreover, the reverse sequence of Pac-525, Ac-IWRVWRRWK-NH2, designated as Pac-525rev, and two Pac-525 diastereomers, D-Pac-525 and D-Nal-Pac-525, derived from Pac-525 are also potent antibacterial agents against Gram-positive and Gram-negative bacteria; furthermore D-Nal-Pac-525 is highly active for antifungi, but displayed high haemolysis. The solution structure of D-Nal-Pac-525 bound to DPC micelles forms an □-helical segment at residues Lys1, Nal2, Arg3, Arg4, Nal5, Val6 and Arg7 and displayed an apparent amphipathic conformation. All hydrophobic residues including Nal2, Nal5, Val6, Nal8 and Ile9 formed a hydrophobic core. Visualized images of the peptides and bacteria on the electron microscopy present that Nal-substituted and Trp-containing peptides, D- Nal-Pac-525, Pac-525 and D-Pac-525, might proceed through membrane via the different modes and they indeed interacted with the membrane of bacteria. Our results indicate that the chirality of Pac-525 did not play a role in antibacterial activity and the aromatic chain of □-naphthylalanine makes the peptide to change and add the specificity of eukaryotic membrane.
Src homology 2 (SH2) domains play an important role in transduction pathways and Grb2 is required for cell transformation by the neu and bcr-abl oncogenes. Therefore, the Grb2 SH2 domain has been chosen as the target for developing the potential agents of breast cancer and other human cancers. Here, the nonphosphorylated peptide inhibitors, linear tetrapeptides and thioether cyclized peptides for Grb2 SH2 domain are presented. The inhibitory effect of linear tetrapeptides with the sequence Fmoc-X-Y-Aib-N-amide on Grb2 SH2 domain were estimated by surface plasmon resonance technology. Using two-dimensional NMR and simulated annealing methods to determine the solution structure of G1TE, a cyclized nonphosphorylated peptides. From the solution structure of G1TE, we suggest that it may from a large circle-like binding surface than the BCR-Abl phosphopeptide in the bound. Further we want to solve the complex structure of the Grb2 SH2 domain and G1TE(Gla1), a analogue of G1TE, and realize the role of cyclized nonphosphorylated peptide in its interaction with the Grb2 SH2. Until now, we are still solving the complex structure of G1TE(Gla1) and Grb2 SH2 domain by NMR and X-ray. These results reveal that the nonphosphorylated linear tetrapeptides are effective antagonists and the structure of thioether cyclized peptide provides a molecular basis understanding, these peptides will serve as the lead structure for the further design of potential antagonists of Grb2 SH2.

Reference
Allen, T. M. (1984). Calcein as a tool in liposome methodology. In LiposomeTechnology G. Gregoriadis, editor, CRCPress, Boca Raton, FL. 177–182.
Andreu, D., and Rivas, L. (1998). Animal antimicrobial peptides: an overview. Biopolymers 47, 415-433.
Bals, R., and Wilson, J. M. (2003). Cathelicidins - a family of multifunctional antimicrobial peptides. Cell Mol. Life Sci. 60, 711-720.
Blondelle, S., and Lohner, K. (2000). Combinatorial libraries: a tool to design antimicrobial and antifungal peptide analogues having lytic specificities for structure-activity relationship studies. Biopolymers 55, 74-87.
Brock, T. D. (1974). Biology of Microorganisms, 2nd ed. Prentice-Hall Inc., Englewood Cliffs, N.J.
Buday, L., and Downward, J. (1993). Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73(3), 611-20.
Burstein, E. A., Vedenkina, N. S., and Ivkova, M. N. (1973). Fluorescence and the location of tryptophan residues in protein molecules. Photochem Photobiol 18(4), 263-79.
Chardin, P., Cussac, D., Maignan, S., and Ducruix, A. (1995). The Grb2 adaptor. FEBS Lett 369(1), 47-51.
Cowburn, D. (1995). Src homology adaptor proteins: more than the sum of the parts? Structure 3(5), 429-30.
Daly, R. J., Binder, M. D., and Sutherland, R. L. (1994). Overexpression of the Grb2 gene in human breast cancer cell lines. Oncogene 9(9), 2723-7.
Dathe, M., Nikolenko, H., Klose, J., and Bienert, M. (2004). Cyclization increases the antimicrobial activity and selectivity of arginine- and tryptophan-containing hexapeptides. Biochemistry 43(28), 9140-50.
Eftink, M. R., and Ghiron, C. A. (1976). Exposure of tryptophanyl residues in proteins. Quantitative determination by fluorescence quenching studies. Biochemistry 15(3), 672-80.
Egan, S. E., Giddings, B. W., Brooks, M. W., Buday, L., Sizeland, A. M., and Weinberg, R. A. (1993). Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363(6424), 45-51.
El Jastimi, R., Edwards, K., and Lafleur, M. (1999). Characterization of permeability and morphological perturbations induced by nisin on phosphatidylcholine membranes. Biophys J 77(2), 842-52.
Epand, R. M., and Vogel, H. J. (1999). Diversity of antimicrobial peptides and their mechanisms of action. Biochim. Biophys. Acta 1462, 11-28.
Fernandez-Lopez, S., Kim, H. S., Choi, E. C., Delgado, M., Granja, J. R., Khasanov, A., Kraehenbuehl, K., Long, G., Weinberger, D. A., Wilcoxen, K. M., and Ghadiri, M. R. (2001). Antibacterial agents based on the cyclic D,L-alpha-peptide architecture. Nature 412(6845), 452-5.
Fimland, G., Eijsink, V. G., and Nissen-Meyer, J. (2002). Mutational analysis of the role of tryptophan residues in an antimicrobial peptide. Biochem. 41, 9508-9515.
Friedrich, C. L., Rozek, A., Patrzykat, A., and Hancock, R. E. W. (2001). Structure and mechanism of action of an indolicidin peptide derivative with improved activity against gram-positive bacteria. J. Biol. Chem. 276, 24015-24022.
Furet, P., Gay, B., Caravatti, G., Garcia-Echeverria, C., Rahuel, J., Schoepfer, J., and Fretz, H. (1998). Structure-based design and synthesis of high affinity tripeptide ligands of the Grb2-SH2 domain. J Med Chem 41(18), 3442-9.
Furet, P., Gay, B., Garcia-Echeverria, C., Rahuel, J., Fretz, H., Schoepfer, J., and Caravatti, G. (1997). Discovery of 3-aminobenzyloxycarbonyl as an N-terminal group conferring high affinity to the minimal phosphopeptide sequence recognized by the Grb2-SH2 domain. J Med Chem 40(22), 3551-6.
Gale, N. W., Kaplan, S., Lowenstein, E. J., Schlessinger, J., and Bar-Sagi, D. (1993). Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature 363(6424), 88-92.
Ganz, T. (2003). Defensins: antimicrobial peptides of innate immunity. Nature Rev. Immunol. 3, 710-720.
Gay, B., Furet, P., Garcia-Echeverria, C., Rahuel, J., Chene, P., Fretz, H., Schoepfer, J., and Caravatti, G. (1997). Dual specificity of Src homology 2 domains for phosphotyrosine peptide ligands. Biochemistry 36(19), 5712-8.
Gishizky, M. L., Cortez, D., and Pendergast, A. M. (1995). Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation. Proc Natl Acad Sci U S A 92(24), 10889-93.
Gram, H., Schmitz, R., Zuber, J. F., and Baumann, G. (1997). Identification of phosphopeptide ligands for the Src-homology 2 (SH2) domain of Grb2 by phage display. Eur J Biochem 246(3), 633-7.
Hancock, R. E., and Lehrer, R. (1998). Cationic peptides: a new source of antibiotics. Trends Biotechnol 16(2), 82-8.
Hancock, R. E. W., and Patrzykat, A. (2002). Clinical development of cationic antimicrobial peptides: from natural to novel antibiotics. Curr. Drug. Targets infect. disorders 2, 79-83.
Hope, M. J., Bally, M.B., Webb, G. and Cullis, P.R. (1985). Production of large unilamellar vesicles by a rapid extrusion procedure: Characterization of size, trapped volume and ability to maintain a membrane potential. Biochim. Biophys. Acta 812, 55-65.
Hwang, P. M., Zhou, N., Shan, X., Arrowsmith, C. H., and Vogel, H. J. (1998). Three-dimensional solution structure of Lactoferricin B, an antimicrobial peptide derived from Bovine Lactoferrin. Biochem. 37, 4288-4298.
Iwahori, A., Hirota, Y., Sampe, R., Miyano, S., and Numao, N. (1997). Synthesis of reversed magainin 2 analogs enhanced antibacterial activity. Biol Pharm Bull 20(3), 267-70.
Janes, P. W., Daly, R. J., deFazio, A., and Sutherland, R. L. (1994). Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. Oncogene 9(12), 3601-8.
Jing, W., Demcoe, A. R., and Vogel, H. J. (2003). Conformation of a bactericidal domain of puroindoline a: structure and mechanism of action of a 13-residue antimicrobial peptide. J. Bacteriology 185, 4938-4947.
Jing, W., Hunter, H. N., Hagel, J., and Vogel, H. J. (2003). The structure of the antimicrobial peptide Ac-RRWWRF-NH2 bound to micelles and its interactions with phospholipid bilayers. J. Pept. Res. 61, 219-229.
Killian, J. A., and von Heijne, G. (2000). How proteins adapt to a membrane-water interface. Trends Biochem Sci 25(9), 429-34.
Koradi, R., Billeter, M., and Wuthrich, K. (1996). MOLMOL: a program for display and analysis of macromolecular structures. J Mol Graph 14(1), 51-5, 29-32.
Lakowicz, J. R. (1999). Principles of fluorescence spectroscopy. Plenum Press, New York, N.Y.
Laskowski, R. A., Rullmannn, J. A., MacArthur, M. W., Kaptein, R., and Thornton, J. M. (1996). AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 8(4), 477-86.
Li, P., Zhang, M., Long, Y. Q., Peach, M. L., Liu, H., Yang, D., Nicklaus, M., and Roller, P. P. (2003a). Potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics. Bioorg Med Chem Lett 13(13), 2173-7.
Li, P., Zhang, M., Peach, M. L., Zhang, X., Liu, H., Nicklaus, M., Yang, D., and Roller, P. P. (2003b). Structural basis for a non-phosphorus-containing cyclic peptide binding to Grb2-SH2 domain with high affinity. Biochem Biophys Res Commun 307(4), 1038-44.
Lou, Y. C., Lung, F. D., Pai, M. T., Tzeng, S. R., Wei, S. Y., Roller, P. P., and Cheng, J. W. (1999). Solution structure and dynamics of G1TE, a nonphosphorylated cyclic peptide inhibitor for the Grb2 SH2 domain. Arch Biochem Biophys 372(2), 309-14.
Lowenstein, E. J., Daly, R. J., Batzer, A. G., Li, W., Margolis, B., Lammers, R., Ullrich, A., Skolnik, E. Y., Bar-Sagi, D., and Schlessinger, J. (1992). The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70(3), 431-42.
Lung, F. D., Tsai, J. Y., Wei, S. Y., Cheng, J. W., Chen, C., Li, P., and Roller, P. P. (2002). Novel peptide inhibitors for Grb2 SH2 domain and their detection by surface plasmon resonance. J Pept Res 60(3), 143-9.
Maignan, S., Guilloteau, J. P., Fromage, N., Arnoux, B., Becquart, J., and Ducruix, A. (1995). Crystal structure of the mammalian Grb2 adaptor. Science 268(5208), 291-3.
Margolis, B. (1994). The GRB family of SH2 domain proteins. Prog Biophys Mol Biol 62(3), 223-44.
Merrifield, E. L., Mitchell, S. A., Ubach, J., Boman, H. G., Andreu, D., and Merrifield, R. B. (1995). D-enantiomers of 15-residue cecropin A-melittin hybrids. Int J Pept Protein Res 46(3-4), 214-20.
Mitchell, J. B., and Smith, J. (2003). D-amino acid residues in peptides and proteins. Proteins 50(4), 563-71.
NCCLS (1993). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Third Edition. Approved Standard M7-A3, National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania.
Nilges, M., Clore, G. M., and Gronenborn, A. M. (1988). Determination of three-dimensional structures of proteins from interproton distance data by dynamical simulated annealing from a random array of atoms. Circumventing problems associated with folding. FEBS Lett 239(1), 129-36.
Nilges, M., Kuszewski, J., and Brunger, A. T. (1991). Computational Aspects of the Study of Biological Macromolecules by NMR. Plenum Press, New York.
Ogura, K., Tsuchiya, S., Terasawa, H., Yuzawa, S., Hatanaka, H., Mandiyan, V., Schlessinger, J., and Inagaki, F. (1997). Conformation of an Shc-derived phosphotyrosine-containing peptide complexed with the Grb2 SH2 domain. J Biomol NMR 10(3), 273-8.
Oligino, L., Lung, F. D., Sastry, L., Bigelow, J., Cao, T., Curran, M., Burke, T. R., Jr., Wang, S., Krag, D., Roller, P. P., and King, C. R. (1997). Nonphosphorylated peptide ligands for the Grb2 Src homology 2 domain. J Biol Chem 272(46), 29046-52.
Oren, Z., and Shai, Y. (1997). Selective lysis of bacteria but not mammalian cells by diastereomers of melittin: structure-function study. Biochemistry 36(7), 1826-35.
Pawson, T., and Schlessingert, J. (1993). SH2 and SH3 domains. Curr Biol 3(7), 434-42.
Pelicci, G., Giordano, S., Zhen, Z., Salcini, A. E., Lanfrancone, L., Bardelli, A., Panayotou, G., Waterfield, M. D., Ponzetto, C., Pelicci, P. G., and et al. (1995). The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene 10(8), 1631-8.
Pelicci, G., Lanfrancone, L., Grignani, F., McGlade, J., Cavallo, F., Forni, G., Nicoletti, I., Grignani, F., Pawson, T., and Pelicci, P. G. (1992). A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70(1), 93-104.
Phan, J., Shi, Z. D., Burke, T. R., Jr., and Waugh, D. S. (2005). Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2 SH2 Domain. J Mol Biol 353(1), 104-15.
Prenner, E. J., Kiricsi, M., Jelokhani-Niaraki, M., Lewis, R. N., Hodges, R. S., and McElhaney, R. N. (2005). Structure-activity relationships of diastereomeric lysine ring size analogs of the antimicrobial peptide gramicidin S: mechanism of action and discrimination between bacterial and animal cell membranes. J Biol Chem 280(3), 2002-11.
Rahuel, J., Gay, B., Erdmann, D., Strauss, A., Garcia-Echeverria, C., Furet, P., Caravatti, G., Fretz, H., Schoepfer, J., and Grutter, M. G. (1996). Structural basis for specificity of Grb2-SH2 revealed by a novel ligand binding mode. Nat Struct Biol 3(7), 586-9.
Rozakis-Adcock, M., McGlade, J., Mbamalu, G., Pelicci, G., Daly, R., Li, W., Batzer, A., Thomas, S., Brugge, J., Pelicci, P. G., and et al. (1992). Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 360(6405), 689-92.
Rozek, A., Friedrich, C. L., and Hancock, R. E. W. (2000). Structure of the bovine antimicrobial peptide indolicidin bound to dodecylphosphocholine and sodium dodecyl sulfate micelles. Biochem. 39, 15765-15774.
Sastry, L., Lin, W., Wong, W. T., Di Fiore, P. P., Scoppa, C. A., and King, C. R. (1995). Quantitative analysis of Grb2-Sos1 interaction: the N-terminal SH3 domain of Grb2 mediates affinity. Oncogene 11(6), 1107-12.
Schibli, D. J., Epand, R. F., Vogel, H. J., and Epand, R. M. (2002). Tryptophan-rich antimicrobial peptides: comparative properties and membrane interactions. Biochem. Cell Biol. 80, 667-677.
Schibli, D. J., Hwang, P. M., and Vogel, H. J. (1999a). The structure of the antimicrobial active center of lactoderricin B bound to sodium dodecyl sulfate micelles. FEBS Lett. 446, 213-217.
Schibli, D. J., Hwang, P. M., and Vogel, H. J. (1999b). Structure of the antimicrobial peptide tritrpticin bound to micelles: a distinct membrane-bound peptide fold. Biochem. 38, 16749-16755.
Schiering, N., Casale, E., Caccia, P., Giordano, P., and Battistini, C. (2000). Dimer formation through domain swapping in the crystal structure of the Grb2-SH2-Ac-pYVNV complex. Biochemistry 39(44), 13376-82.
Schlaepfer, D. D., Hanks, S. K., Hunter, T., and van der Geer, P. (1994). Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372(6508), 786-91.
Shai, Y. (2002). From innate immunity to de-novo designed antimicrobial peptides. Curr Pharm Des 8(9), 715-25.
Shai, Y., and Oren, Z. (1996). Diastereoisomers of cytolysins, a novel class of potent antibacterial peptides. J Biol Chem 271(13), 7305-8.
Songyang, Z., Shoelson, S. E., Chaudhuri, M., Gish, G., Pawson, T., Haser, W. G., King, F., Roberts, T., Ratnofsky, S., Lechleider, R. J., and et al. (1993). SH2 domains recognize specific phosphopeptide sequences. Cell 72(5), 767-78.
Subbalakshmi, C., Krishnakumari, V., Nagaraj, R., and Sitaram, N. (1996). Requirements for antibacterial and hemolytic activities in the bovine neutrophil derived 13-residue peptide indolicidin. FEBS Lett 395(1), 48-52.
Tinoco, L. W., da Silva Jr., A., Leite, A., Valente, A. P., and Almeida, F. C. L. (2002). NMR structure of PW2 bound to SDS micelles. J. Biol. Chem. 277, 36351-36356.
Tossi, A., Sandri, L., and Giangaspero, A. (2000). Amphipathic, a-helical antimicrobial peptides. Biopolymers 55, 4-30.
Wade, D., Boman, A., Wahlin, B., Drain, C. M., Andreu, D., Boman, H. G., and Merrifield, R. B. (1990). All-D amino acid-containing channel-forming antibiotic peptides. Proc Natl Acad Sci U S A 87(12), 4761-5.
Waksman, G., Shoelson, S. E., Pant, N., Cowburn, D., and Kuriyan, J. (1993). Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms. Cell 72(5), 779-90.
Wessolowski, A., Bienert, M., and Dathe, M. (2004). Antimicrobial activity of arginine- and tryptophan-rich hexapeptides: the effects of aromatic clusters, D-amino acid substitution and cyclization. J Pept Res 64(4), 159-69.
Wieprecht, T., Apostolov, O., Beyermann, M., and Seelig, J. (2000). Membrane binding and pore formation of the antibacterial peptide PGLa: thermodynamic and mechanistic aspects. Biochemistry 39(2), 442-52.
Wiseman, T., Williston, S., Brandts, J. F., and Lin, L. N. (1989). Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal Biochem 179(1), 131-7.
Woody, R. W. (1994). Contributions of tryptophan side chains to the far-ultraviolet circular dichroism of proteins. Eur Biophys J 23(4), 253-62.
Wuthrich, K. (1986). NMR of Proteins and Nucleic Acids. John Wiley & Sons, New York, USA.
Xie, Y., Pendergast, A. M., and Hung, M. C. (1995). Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu. J Biol Chem 270(51), 30717-24.
Yao, Z. J., King, C. R., Cao, T., Kelley, J., Milne, G. W., Voigt, J. H., and Burke, T. R., Jr. (1999). Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. J Med Chem 42(1), 25-35.
Zasloff, M. (2002). Antimicrobial peptides of multicellular organisms. Nature 415, 389-395.